The gamma chain gene of the interleukin-2 receptor (IL2RG) is the disease gene for X-linked severe combined immunodeficiency (SCID). This is the most common of several gene defects causing the SCID syndrome, which occurs in 1 in 10,000 to 100,000 births. Males with X-linked SCID generally die of persistent and opportunistic infections in the first year of life unless they are rescued by bone marrow transplantation. New mutations account for a substantial proportion of cases. Detection of IL2RG mutations in SCID males allows: 1) definition of X-linked SCID clinical features within the spectrum of all SCID; ii) study of specific mutations with regard to frequency and clinical severity; iii) participation in the evolving management of SCID families, including devising and performing carrier and prenatal testing; iv) monitoring utilization of genetic services by X-linked SCID families; and v) planning new therapeutic approaches. Research efforts have been aimed at mutation detection by single strand conformation polymorphism and dideoxy fingerprinting, with 87 unrelated patient mutations detected to date. Unique genetic features including germ line mosaicism, a branch point A mutation and 5 mutation hot spots have been found. Prenatal monitoring of at-risk pregnancies has allowed for implementation of neonatal bone marrow transplantation, with improved results over typical transplants. Moreover, a new and promising in utero transplantation was made possible through collaboration with Alan Flake, MD, of Wayne State University Medical School. An affected male fetus was treated in utero with paternal CD34+ cells administered intraperitoneally at 17-20 week of pregnancy. A term, healthy infant, with functional paternal lymphocytes, is now over 1 year old. Ongoing genotype/phenotype correlation studies will show whether particular subsets of SCID patients are likely to benefit from retroviral gene therapy.